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Cited by 83Hair Growth and DisordersGenomics and Chromatin DynamicsSingle-cell and spatial transcriptomics

Integrated single-cell chromatin and transcriptomic analyses of human scalp identify gene-regulatory programs and critical cell types for hair and skin diseases

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Ober-Reynolds, Benjamin, Wang, Chen, Ko, Justin M., Rios, Eon J., Aasi, Sumaira Z., Davis, Mark M., Oro, Anthony E., Greenleaf, William J.·2023·Nature Genetics
DOI 10.1038/s41588-023-01445-4PMC PMC11190942
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Abstract

Genome-wide association studies have identified many loci associated with hair and skin disease, but identification of causal variants requires deciphering of gene-regulatory networks in relevant cell types. We generated matched single-cell chromatin profiles and transcriptomes from scalp tissue from healthy controls and patients with alopecia areata, identifying diverse cell types of the hair follicle niche. By interrogating these datasets at multiple levels of cellular resolution, we infer 50-100% more enhancer-gene links than previous approaches and show that aggregate enhancer accessibility for highly regulated genes predicts expression. We use these gene-regulatory maps to prioritize cell types, genes and causal variants implicated in the pathobiology of androgenetic alopecia (AGA), eczema and other complex traits. AGA genome-wide association studies signals are enriched in dermal papilla regulatory regions, supporting the role of these cells as drivers of AGA pathogenesis. Finally, we train machine learning models to nominate single-nucleotide polymorphisms that affect gene expression through disruption of transcription factor binding, predicting candidate functional single-nucleotide polymorphism for AGA and eczema.

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  • scRNA-seq enables profiling of gene expression at single-cell resolution and identification of reliable cellular heterogeneity, allowing identification of previously unrecognized heterogeneity, revealing regulatory relationships between genes, and tracking trajectories of distinct cell lineages.

    “It enables both profiling of gene expression measurements at a single-cell resolution and identification of reliable cellular heterogeneity, allowing for the identification of previously unrecognized levels of cellular heterogeneity, revealing regulatory relationships between genes, and tracking the trajectories of distinct cell lineages in the same or different developmental stages [63–66].”

    From Diversity of human skin three-dimensional organotypic cultures (2024) · cites this paper as [65]

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Authors
Ober-Reynolds, B., Wang, C., Ko, J. M., Rios, E. J., Aasi, S. Z., Davis, M. M., Oro, A. E., & Greenleaf, W. J.
Affiliations
  • Santa Clara Valley Medical Center (US)
  • Stanford Medicine (US)
  • Howard Hughes Medical Institute (US)
  • Chan Zuckerberg Biohub San Francisco (US)
Corresponding author
Greenleaf, William J.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2023-07-27
Volume
55
Issue
8
Pages
1288-1300
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-023-01445-4
PMC
PMC11190942
OpenAlex
W4385302662
Cited by
83
References
19
Citations by year
2026: 34 · 2025: 26 · 2024: 23
FWCI
26.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (RM1-HG007735, UM1-HG009436, U01-HG011762)
  • U.S. Department of Health & Human Services | National Institutes of Health (R01-HG00990901, T32-GM007365, T32-GM145402, 2R37-ARO54780)
  • U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (U19-AI057266)
  • W.J.G. acknowledges support as a Chan-Zuckerberg Investigator
  • C.W. was supported in part by a Dermatology Foundation Physician Scientist Career Development Award
Topics
  • Health Sciences › Medicine › Urology › Hair Growth and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
alopecia areata, androgenetic alopecia, atopic dermatitis, dermal papilla, enhancer accessibility, gene regulatory networks, transcription factor binding, single nucleotide polymorphisms, causal variants, scalp, hair disorders, skin diseases
MeSH terms
Alopecia Areata, Chromatin, Eczema, Humans, Scalp, Hair Follicle, Genome-Wide Association Study, Transcriptome

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